One out of every four adults in the United States has hypertension and is at increased risk for the development of end-stage renal disease. Although great strides have been made in providing more effective treatments for hypertension, chronic elevation in blood pressure still results in progressive renal damage. Recent reports indicate that the pro-inflammatory cytokine, interleukin-6 (IL-6), plays an important role in renal injury and chronic hypertension. Peroxisome proliferator-activated receptor (PPAR)-alpha is a nuclear hormone-activated receptor and transcription factor that inhibits, IL-6 production, oxidative stress and has been implicated in blood pressure regulation. In the kidney, PPAR-alpha is expressed most abundantly in the proximal tubule segment of the nephron. However, the mechanism by which PPAR-alpha regulates renal-dependent chronic hypertension is not well-understood. We present new data in our PPAR-alpha knockout (KO) mouse model of chronic Angiotensin II (Angll)-induced hypertension that shows an increased pressor response and plasma IL-6 when compared to wild-type (WT) controls. Our new findings indicate that the PPAR-alpha ligand, fenofibrate, lowers the blood pressure response to Angll and plasma IL-6 in WT mice. During Angll + fenofibrate treatment, urinary Na+ excretion is elevated in WT mice when compared to PPAR-alpha KO mice. Therefore, the overall goal of this proposal is to determine the renal mechanisms by which PPAR-alpha reduces chronic hypertension through an IL-6 dependent pathway. We will conduct chronic blood pressure measurements and utilize the single nephron micro puncture technique to test the central hypothesis that PPAR-alpha activation decreases chronic Angll-induced hypertension by decreasing circulating IL-6 and Na+ re-absorption in the proximal tubule. In this proposal, three specific aims are formulated to: 1) test the hypothesis that PPAR-alpha activation decreases Angll-induced hypertension through an IL-6 dependent mechanism, 2) determine the mechanisms responsible for the increased blood pressure in PPAR-alpha KO mice during Angll treatment 3) test the hypothesis that the proximal tubule re-absorption of Na+ is attenuated during PPAR-alpha activation. Our results suggest that understanding the mechanisms involved in PPAR-alpha activation is an important factor for treating hypertension and could provide useful therapeutic agents for the treatment of end-stage renal disease. (End of Abstract)